Despite widespread prevalence of hallucinogenic drug abuse and serious potential hazard to public health, relatively little is known about the mechanisms underlying hallucinogenic drug action. This lack of knowledge, combined with the profound cognitive and behavioral effects of hallucinogens, mandate a need to develop novel approaches to gain a more comprehensive understanding of the behavioral pharmacology of hallucinogenic drugs in vivo. We propose the extensive development of adult zebrafish models to study the behavioral and physiological components of hallucinogenic drug action. Most recently, we have performed preliminary investigations examining the effects of LSD on adult zebrafish. These results demonstrate the utility of adult zebrafish in hallucinogenic drug studies, as these animals exhibit robust behavioral and neuroendocrine responses resulting from LSD exposure. Based on these results, we are interested in expanding upon this line of research to include additional hallucinogenic drugs, including MDMA, mescaline, phencyclidine, and psilocybin. The innovative nature of this research proposal is in its use of adult zebrafish to investigate the effects of hallucinogenic drug exposure across multiple behavioral domains. Paralleling behavioral and physiological responses in zebrafish, a model vertebrate species that shows remarkable homology to humans and exhibits robust behavioral phenotypes, the implications of this study have the potential to contribute to our comprehension of hallucinogenic drug action in ways not possible using more traditional approaches. Ultimately, this may translate into the development of more effective means of diagnosis and treatment for hallucinogenic drug abuse and hallucinogen-induced psychoses. Finally, this research project may also serve to develop high-throughput drug screens for novel pro- and anti-hallucinogenic agents. PUBLIC HEALTH RELEVANCE: This project is aimed at the improved understanding of hallucinogenic drug action through the development and characterization of novel fish-based models of hallucinogenic drug exposure. Analysis of behavioral and physiological phenotypes affected in adult zebrafish (Danio rerio) by several common hallucinogens, we will gain important insights into the neurobiological mechanisms responsible for hallucinogenic drug action. Such knowledge is crucial for the development of better treatments and diagnostics for drug-induced psychoses, and it may foster the expansion of adult zebrafish-based psychotropic drug screens.